Direct acylation of heterocyclic bases



United States Patent 3,120,527 DIRECT ACYLATEON OF HETEROQYCLIC BAfiES Gunave B. Baehman, West Lafayette, End, and Robert M. Schisla, Dayton, Ohio, assignors to Purdue Research Foundation, West Lafayette, Ind., a corporation of lndiana No Drawing. Filed Oct. 20, 1358, Ser. No. 763,066 4 Claims. (Cl. 266-279) This invention relates to direct nuclear substitution of heterocyclic bases and more particularly concerns direct acylation of heterocyclic bases, such as pyridine, quinoline, and related compounds in the presence of a reactive metal catalyst.

Previous attempts at direct substitution of pyridine with compounds such as herein employed have been unsuccessful. Notable among these has been the Friedel-Crafts type reaction. The only successful methods have been by syntheses involving two or more steps. This is cumbersome, expensive and results in comparatively poor overall yields. One such method involves oxidation of a hydrocarbon-radical-substituted pyridine with potassium permanganate. This is expensive and must be preceded by the formation of the hydrocarbon-radical-substituted pyridine before oxidation.

The principal object of the present invention is the direct acylation of a pyridine ring by compounds novel for this purpose.

Another object is to provide a method wherein the substitution products are obtained in good yield.

Another object is to provide an economical method of accomplishing the above objects.

These and other objects are accomplished by this invention and will be readily apparent from the ensuing discussion.

The invention in its broadest concept is a method for direct ring substitution of compounds with the structure:

in which X, Y, and Z represent substituents, at least one of which is a replaceable hydrogen atom, said method comprising the reaction of said compounds under substantially anhydrous conditions with anions produced from acid derivatives and compounds likened to acid derivatives in the presence of metals which will act as both reducing and co-ordinating or chelating agents.

Generally speaking, applicants have discovered the broad and fundamental process wherein pyridine-type compounds may be reacted with acid derivatives and compounds likened to acid derivatives to obtain directly a product nuclearly substituted by an acyl group. Such a direct substitution has not been possible heretofore by such reactants. Certain other substitutions have been possible by direct substitution, such as bromination, nitration, mercuration, and hydrocarbon-radical substitution by coupling and the like. But even these are done only with some difficulty.

The difliculty of performing certain reactions on pyridine is unquestionably accountable to the nitrogen atom of the ring.

The inventors have hypothesized and theorized relative to this and subsequently how acylation may be achieved directly, and the possible mechanism of such a reaction.

3,12%,527 Patented Feb. 4, 19%4 These hypotheses and theories, inclusive of mechanism, are to be herein set forth; however it is to be understood that this is only proposed for scholarly enlightenment of the art. The discoverers by doing so hope to provoke thoughts which will result in further advances in the art. It is possible, despite the experimental evidence in support theretof, that these hypotheses, theories, and proposed mechanisms are in error at least in part. For this reason, such advanced forth hypotheses, theories, and proposed mechanism are to be in no way limiting to their invention; the invention in final analysis teaches, for example, that pyridine-type compounds may be substituted directly by compounds such as esters, N,N-dialkylamides, and nitriles in the presence of certain metals. The art is taught how definite desired results may be obtained, regardless of theory in such a manner that these and similar results may be duplicated.

It was postulated by applicants that the ring member N= of pyridine-type compounds is sufficiently electrophilic in nature to deactivate the remainder of the ring to attack by cations, thus explaining the inoperability of conventional substitution techniques. It occurred to them, therefore, that direct substitution, in particular acylation, of pyridines might be achieved satisfactorily if carbanions, in particular acyl ions or the like, could be created in the presence of these heterocyclic bases. One method of approach to such would be according to the hypothesis of G. B. Bachman, R. M. Schisla, M. Hamer, and E. Dunning, the former two being the same Bachman and Schisla, inventors of the instant application. This comprises treating the acylating agent with a metal capable of reducing, say carbonyl, groups by a two-electron transfer to form a carbanion thereby.

The success of the reaction involving pyridine, N,N dimethyl benzamide, and amalgamated magnesium catalyst was first announced in Journal of Organic Chemistry, 22, 858 (July 1957), under authorship of applicants. Since that time, the reaction has been greatly extended and preferred embodiments discovered as well, some of which was reported in Journal of Organic Chemistry, 22, 1302 (November 1957).

The metals suitable as catalysts are multivalent, having a reducing potential greater than manganese and a coordinating power greater than calcium. Preferred metals are aluminum and magnesium. Co-ordinating power may be defined as complexing ability with organic materials. Aluminum is the most preferred catalyst by reason of its generally beneficial improvement in yields over the other operable catalysts. Most of the suitable metals are sutficiently reactive; that, on exposure to air, they normally acquire an oxide coating. In many instances, these oxide coatings are protective; that is, they prevent reaction. For this reason, they are employed as amalgams, although it may be found sufficient to merely expose clean surfaces of the metals. In this connection, means to provide clean surfaces will be needed. These are well known to the art.

The catalyst having been defined in a broad and generic manner, it should be pointed out to prevent this from being misleading that all of the defined metals will not give equal results in all instances. Some discretion must be employed in selecting the catalyst for the particular pyridine and reactant contemplated. For N,N-dialkylamides, very often the preferred catalyst is magnesium; however, for the most part, in all other cases, aluminum is the preferred catalyst. Some exceptions to this will be found.

Representative of the mechanism believed to be involved is the following, shown with respect to ethyl benzoate, pyridine, and magnesium as catalyst:

As can be seen, the reaction appears to proceed through complexes or metal chelates intermediates to produce the acylated pyridine compound.

Recovery of the products may be worked up by many methods readily apparent to those skilled in the art, such as by cooling the reaction products, hydrolyzing with a base, acid extracting, basifying, and finally fractional distillation of the nitrogenous products. We, however, have found the preferred method of workup involves first isolating the metallic complex before hydrolyzing by pouring the reaction mixture into a precipitant such as petroleum ether, preferably in four to five volumes of the ether. Such a method does have a rather insignificant deleterious result of 35 percent lower yields, but this is far outweighed by the advantages of convenient and facilitory procedures, more rapid results, and a cleaner product (which is almost always desirable) than direct hydrolysis. In the end, it may be found that at least in some cases over-all yield is even better when the same degree of purity is desired; however, on occasion, to some extent, the Workup may be varied somewhat in view of the many independent factors which may enter under certain circumstances and cause a party to prefer one method over the other. It should be remembered, however, that in some cases the use of a precipitant such as petroleum ether is rather essential to the process.

It may be found desirable in some cases to recover the catalyst metal, which in ultimately a metal hydroxide and convert it back in a reusable form. Such may be found economically advantageous. Such recovery and conversion should present little difiiculty to those skilled in the alt.

Simultaneously produced in many instances are valuable by-produets which further enhances the desirability of this newly discovered process herein. These, for example, in some cases are products such as acetoin, pinacol, bipyridyl, benzoin, and benzil which, when obtained, are generally produced in minor but significant quantities which greatly enhances the economics of the process. The experience of by-products such as benzoin and benzil suggests that some single-electron transfer occurs simultaneously with at least some metal catalysts. Homogeneous bimolecular reduction products, such as in some cases benzil and benzoin, result thereby. Naturally, those metals which produce a predominance of substituted pyridines and lesser by-products are for the most part to be preferred. The following proposed mechanism may serve to if, more clearly explain the by-products produced by the reaction as, for example, benzil and benzoin.

Usually, progress of the process may be observed by the appearance of a coloration sequence, which ensues when pyridine and say acylating agent are added to the catalyst metal. The particular color observed depends on the metal chelates formed. This coloration may assist an operator engaged in the practice of the process herein; but the process is, in most cases, considered complete when the metal disappears. Nevertheless, the reaction is continued until no further change is observed.

Some heat is generally required to cause reaction of the charged reactants. This very often is a temperature of C. It is not unlikely that, in some cases, lower temperatures will sufiice; and still in other cases, temperatures, some in excess of 100 C., will at least be found desirable. The process has been run at room temperature. For the most part, 100 C. or slightly in excess of 100 C. will be found sufficient, convenient, and preferred. Because of the usual need for some heating and ultimately elevated temperatures, pressure will be found desirable with low boiling reactants to keep them in the reaction mixture and consequently in intimate contact. As would be expected, yields are lower when the reactant is not kept in the mixture. Pressure then improves the yield with low boiling reactants. Generally, the pressure required will not be found to be great.

It has been found advantageous to employ an inert diluent in the reaction, however, occasions may arise where this will be unnecessary. The diluent should be inert to the reactants as well as the products, lest deleterious effects are realized. The inert diluent may be excess pyridine inasmuch as the excess is inert in the reaction.

The products of the process may vary somewhat due to the possibility of different isomeric forms of the products. This involves usually the 2- and 4-positions on the pyridine ring. It is possible, in some cases, to get one or the other and, still in some cases, to get a mixture of the isomers. Some of the factors affecting this are steric hindrance due to substituents, and the size of the metal atom involved in the chelation, and others equally recognizable by those skilled in the art.

Representative of the type of nitrogeneous compounds which are suitable in the process are pyridine, picoline, lutidine, quinoline, isoquinoline, benzoquinolines, and acridines.

Preferred compounds are those not having substituents in the 2-position or in both the 2- and 6-positions, as obviously again results would be affected because of steric hindrance. On the other hand, pyridines substituted in the 3- or 4-positions will not encounter substantial steric hindrance; and the yields will therefore be correspondingly better. Nevertheless, pyridine compounds have the following general structural formula will be found to work in this invention:

wherein X, Y, and Z represent substituents, at least one of which is a replaceable hydrogen atom. To explain this more fully: A and B may be H, alkyl, or aryl, either saturated or unsaturated; X, Y, and Z may be H, an alkyl, an aryl, either saturated or unsaturated; X and B, B and Z, Z and A, and A and Y may be joined such as to form a cyclic structure. The first condition, however, must prevail.

Best results are usually obtained with esters, nitriles, and N,N-dialkylamides when reacted with the pyridines containing no other functional groups. In most cases best results are obtained with the aromatics. This has not yet been entirely satisfactorily explained.

The invention may be more fully understood when the following illustrative examples are considered:

EXAMPLE 1 Procedure A Granular aluminum metal (27.0 -g., 1.0 mole) was heated with mercuric chloride (5.0 g.) and several drops of mercury for 2 hours at 100 in a three-necked flask fitted with an addition funnel, condenser, and stirrer. Ethyl benzoate g.) and pyridine (25 g.) were added to the metallic mixture to initiate the reaction. A green color developed immediately and turned to a muddy brown within a few minutes. Pyridine (250 g, 3.5 moles total) was added dropwise over a period of 2 hours, keeping the reaction mixture at total reflux. At the end of this addition, the reaction mixture was dark colored. Ethyl benzoate (425 g., 3.0 moles total) was added dropwise to the reaction mixture over a period of 24 hours, at which time all of the aluminum metal had reacted. The partially cooled reaction mixture was poured into a liter of 6 N sodium hydroxide and the gel that developed was broken up by stirring. The oil layer was separated and extracted several times with 6 N hydrochloric acid.

The acid extracts were made basic with an excess of 6 N sodium hydroxide and the generated oil taken up in ether, dried over potassium hydroxide pellets, and rapidly distilled, eventually under vacuum. The higher boiling distillate was refractionated through a cm. glass-helixpacked column and the fraction boiling at 126*146 (1.9 mm.) was refrigerated. The solid material which crystallized was identified as 4-benzoylpyr idine after recrystallizations from petroleum ether (90-100). This material melted at 72.5-73.0", literature M.P. 71.5-72.6". The picrate derivative melted at -160161, literature M.P. 160.

The mother liquor from this refrigeration was refractionated through a small vigreaux column to give a yellow oil, B.P. l24-126 (1.5 mm), 65.8 g., 23.9 percent yield; 11 1.5940, (1 111458. It was identified as 2-benzolypyridine by preparing *a variety of derivatives including: (a) phenyI-Z-pyridylmethanol hydrochloride, M.P. 180- 181.5, literature M.P. l82l84, (b) phenyl-Z-piperidylmethanol hydrochloride, M.P. 199.5-201, literature M.P. ZOO-202 for this enant-iomorphic pair, (c) 2,4-dinitrophenylhydrazone 196-1975 literature M.P. 196.5- 197.5, and (d) picrate, M.P. 129-130", literature M.P. 130.

Analysis.-Calcd. for C H NozMR 54.47. Found: MR 54.25.

It should be noted that larger amounts of HgCl (0.2 mole per 1 mole of metal) have been used in the catalyst.

, 6 EXAMPLE 2 Procedure B.Is0lation of the Intermediate Complex The same steps were followed as in Example 1, and the same amounts of reactants were used. The cooled reac tion mixture was stripped of unreacted pyridine using an aspirator and mild heating, and then the remaining viscous oil (about 350-400 ml.) was poured into 1500 ml. of petroleum ether (100). This addition resulted in the precipitation of a brown solid (286 grams) which could be filtered, dried, and allowed to stand in the presence of air without any noticeable decomposition. This complex was hydrolyzed with 6 N hydrochloric acid and Worked up in a manner similar to the techniques previously discussed for obtaining 2- and 4-benzoylpyridine. The fololwing products were isolated and identified: Z-benzoylpyridine, 4 benzoylpyr-idine, benzil, and benzoin.

After removal of the excess petroleum ether and unreacted starting material from the filtrate by mild heating under vacuum, the remaining viscous oil was hydrolyzed with 6 N hydrochloric acid and the resulting mixture worked up using previously described techniques. The following products were found: 2-benzoylpyridine, 4- benzoylpyridine, benzil, benzoin in smaller amounts.

Since the 4-isomer was 'found to be present in both the filtrate and the complex, no advantages of separation of the 2- and 4-isomers by isolating the complex could "be found. However, the purity of the 2-isomer obtained from the hydrolysis of the complex was high as evidenced by its molecular refractivity (54.27). The presence of benzil and benzoin in the complex eliminated any possibility of studying the true composition of the pyridine component in the complex.

Similar results have been obtained with ethyl cinnamate, ethyl picolinate, ethyl benzoate (B catalyst), secondarybutyl acetate, n-amyl acetate, 2-ethylhexyl acetate, ethyl propionate, N,N-dimethylbenzamide with quinoline, ethyl benzoate with quinoline, ethyl benzoate with 4-picoline, benzonitrile (an imine is obtained which was hydrolyzed with HCl to the acyl compound).

As can be seen, the esters, N,N-dailkylamides, and nitriles suitable in this process may have. additional substituents. This, as a general rule, is any substituent which will not form an anion in competition with the carbanion forming portion of the molecule.

To illustrate esters and the like having nitro group constituents yield an azo compound rather than a substituted pyridine. Specifically, ethyl p-nitrobenzoate yielded 4,4- di-carbethoxyazobenzene.

What is considered new and inventive in the present invention is defined in the hereunto appended claims, it being understood, of course, that equivalents known to those skilled in the art are to be constructed as within the scope and purview of the claims.

We claim:

1. A process for preparing acylated pyridine compounds by direct substitution which comprises reacting pyridine with a compound selected from the group consisting of ethyl benzoate, ethyl cinnamate, ethyl picolinate, secondary-butyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-amyl acetate, ethyl-p-chloro-benzoate, and benzonitrile, said reaction being conducted at a temperature in the range of about room temperature to about C. and in the presence of a multivalent metal catalyst having an atomic number of at least 12 but not more than '13.

2. A process according to claim 1 wherein the catalyst is aluminum.

3. A process according to claim 1 wherein the aluminum catalyst is in an amalgam with mercuric chloride and mercury.

4. A process for preparing acylated pyridines by direct substitution which comprises reacting a pyridine compound selected from the group consisting of pyridine,

7 5 picoline, lutidine, quinoline, isoquinoline, benzoquinoline, References Cited in the file of this patent and acridines with a compound selected from the group UNITED STATES PATENTS consisting of ethyl benzoate, ethyl cinnamate, ethyl picolinate, secondary-butyl acetate, Z-ethylhexyl acetate, 2663711 1953 ethyl propionate, n-amyl acetate, and benzonitrile, said 5 OTHER REFERENCES reaction being conducted at a temperature in the range of B h t a]; J, Org. Chem, vol. 22, p. 858 (July about room temperature to about 100 C. and in the pres- 1957), ence of a multivalent metal catalyst having an atomic Bachman et 211.: J. Org. Chem, vol. 22, pp. 1302-8 number of at least 12 and not more than 13. (November 1957).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3 12052? February l 1964 Gustave Bo Bachman et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2 line 7 for 'theretof" read thereof column 3 lines 17 to 22 for OC2H5 00 14 @C/ read I\ C/ 1 \N HOMg -O C H5 HOMg O C H lines 23 to 26 for H read I -==CgH C-C H N 5 column. line 56 for "in" read is column 1 lines to 24% for OH 0 OIH F C O SZ C-C H read 115? C H column. o line l7 for "olwing" read lowing line for E15 read Be line 423 for "N .N dai lkylamides" read N l\ldialkylamides column 6 line 54 for construoted read construed same column 6 line 62 strike out 'ethylpchlorodzenzoate",

Signed and sealed this 1st day of September 1964K (SEAL) Attest;

EDWARD JD BRENNER Commissioner of Patents ERNEST W0 SWIDER Attesting Officer 

1. A PROCESS FOR PREPARING ACYLATED PYRIDINE COMPOUNDS BY DIRECT SUBSTITUTION WHCIH COMPRISES REACTING PYRIDINE WITH A COMPUND SELECTED FROM THE GROUP CONSISTING OF EHTYL BENZOATE, ETHYL CINNAMATE, ETHYL PICOLINATE, SECONDARY-BUTYL ACETATE, 2-ETHYLHEXYL ACETATE, ETHYL PROPIONATE, N-AMYL ACETATE, ETHYL-P-CHLORO-BENZOATE, AND BENZONITRILE, SAID REACTION BEING CONDUCTED AT A TEMPERATURE IN THE RANGE OF ABOUT ROOM TEMPERATURE TO ABOUT 100*C. AND IN THE PRESENCE OF A MILTIVALENT METAL CATALYST HAVING AN ATOMIC NUMBER OF AT LEAST 12 BUT NOT MORE THAN
 13. 